Faculty Bibliography

OBJECTIVE:Both drowning and sudden unexpected death in epilepsy (SUDEP) are diagnoses of exclusion with predominantly nonspecific autopsy findings. We hypothesized that people with epilepsy found dead in water with no clear sign of submersion could be misdiagnosed as SUDEP. METHODS:All reported seizure-related deaths undergoing medicolegal investigation in three medical examiner's offices (New York City, Maryland, San Diego County) over different time periods were reviewed to identify epilepsy-related drownings and SUDEPs. Drowning cases that fulfilled inclusion criteria were divided into two groups according to the circumstances of death: definite drowning and possible drowning. The SUDEP group included two sex- and age (±2 years)-matched definite SUDEP/definite SUDEP plus cases for each drowning case. RESULTS:Of 1346 deaths reviewed, we identified 36 definite (76.6%) and 11 possible drowning deaths (23.4%), most of which occurred in a bathtub (72.3%). There were drowning-related findings, including fluid within the sphenoid sinuses, foam in the airways, clear fluid in the stomach content, and lung hyperinflation in 58.3% (21/36) of the definite drowning group, 45.5% (5/11) of the possible drowning group, and 4.3% of the SUDEP group (4/92). There was no difference in the presence of pulmonary edema/congestion between the definite drowning group, possible drowning group, and SUDEP group. The definite drowning group had a higher mean combined lung weight than the SUDEP group, but there was no difference in mean lung weights between the possible drowning and SUDEP groups or between the possible drowning and definite drowning groups. SIGNIFICANCE/CONCLUSIONS:No distinguishable autopsy finding could be found between SUDEPs and epilepsy-related drownings when there were no drowning-related signs and no clear evidence of submersion. SUDEP could be the cause of death in such possible drowning cases. As most drowning cases occurred in the bathtub, supervision and specific bathing precautions could be effective prevention strategies.

Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further show that pharmacologic PI3K or AKT inhibition, but not mTORC1 inhibition, causes a neuronal differentiation delay, mimicking the patient phenotype. Together these data suggest that heterozygous TSC2 mutations disrupt neuronal development, potentially contributing to the disease neuropathology, and that this defect may result from dysregulated PI3K/AKT signaling in neural progenitor cells.

Our visual environment constantly changes, yet we experience the world as a stable, unified whole. How is this stability achieved? It has been proposed that the brain preserves an implicit perceptual memory in sensory cortices [1] which stabilizes perception towards previously experienced states [2,3]. The role of higher-order areas, especially prefrontal cortex (PFC), in perceptual memory is less explored. Because PFC exhibits long neural time constants, invariance properties, and large receptive fields which may stabilize perception against time-varying inputs, it seems particularly suited to implement perceptual memory [4]. Support for this idea comes from a neuroimaging study reporting that dorsomedial PFC (dmPFC) correlates with perceptual memory [5]. But dmPFC also participates in decision making [6], so its contribution to perceptual memory could arise on a post-perceptual, decisional level [7]. To determine which role, if any, PFC plays in perceptual memory, we obtained direct intracranial recordings in six epilepsy patients while they performed sequential orientation judgements on ambiguous stimuli known to elicit perceptual memory [8]. We found that dmPFC activity in the high gamma frequency band (HGB, 70-150 Hz) correlates with perceptual memory. This effect is anatomically specific to dmPFC and functionally specific for memories of preceding percepts. Further, dmPFC appears to play a causal role, as a patient with a lesion in this area showed impaired perceptual memory. Thus, dmPFC integrates current sensory information with prior percepts, stabilizing visual experience against the perpetual variability of our surroundings.

OBJECTIVE:We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS:We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS:(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. SIGNIFICANCE/CONCLUSIONS:This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

The identification and characterization of sudden unexpected deaths in epilepsy (SUDEP) may be improved, helping to optimize prevention and intervention. We set out to assess the frequency and demographic and clinical characteristics of SUDEP cases in a sudden death cohort. All out-of-hospital deaths were investigated from March 1, 2013 to February 28, 2015 in Wake County, NC, attended by the Emergency Medical Services. Cases were screened and adjudicated by three physicians to identify sudden death cases from any cause among free-living adults, aged 18-64. In total, 399 sudden death victims were identified during this two-year period. Seizure history, demographic and clinical characteristics, and healthcare utilization patterns were assessed from death records, emergency response scene reports, and medical records. Sudden death cases with a history of seizures were summarized by an experienced chart abstractor (SC) and adjudicated by an experienced neurologist (OD). We then compared demographic and clinical characteristics and healthcare utilization patterns of neurologist-identified SUDEP cases to other sudden death victims in our population-based registry of sudden death from any cause. SUDEP accounted for 5.3% of sudden deaths. However, seizures or complications of seizures were only considered the primary cause of death on death certificates in 1.5% of sudden deaths. SUDEP cases were more likely to have a history of alcohol abuse. Mental health disorders and a low level of medication compliance and healthcare utilization were common among SUDEP victims. SUDEP accounts for approximately 5.3% of sudden deaths from any cause in individuals aged between 18 and 64. Death certificates underestimate the burden of sudden death in epilepsy, attributing only 1.5% of sudden deaths to seizures or complications of seizures. Accurate documentation of epileptic disorders on death certificates is essential for the surveillance of SUDEP. Further, interventions that promote better use of medical services and patient engagement with healthy living practices may reduce sudden deaths in epilepsy.

OBJECTIVE:Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS:Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS:Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE/CONCLUSIONS:Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.